Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems

Definitions

• the present invention relates to compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2).
• JH2 pseudokinase domain
• TYK2 non-receptor tyrosine-protein kinase 2
• Additional aspects of the invention include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes useful in the synthesis of the compounds.
• IFN-a, IFN-b, IFN-K, IFN-d, IFN-e, IFN-t, IFN-co, and IFN-z also known as limitin
• interleukins e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF.
• the activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT3, STAT4, and STAT6.
• Compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the present disclosure are inhibitors of TYK2. In some embodiments, compounds are selective for TYK2 over other JAKs. For example, compounds may bind specifically to the pseudokinase domain (JH2) of TYK2 thereby enhancing selectivity over JAK family members. In some embodiments, a compound of the present disclosure may be an allosteric modulator or noncompetitive inhibitor of TYK2. In additional embodiments, a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders.
• R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle;
• B 1 is N or CR 12a ;
• B 2 is N or CR 12b ;
• R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;
• R 15 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl; or R 14 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; or R 1 and R 15 are taken together with the intervening atoms to which they are
• W is -NR 3 - or -0-;
• R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle; or R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; or R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5- or 6-membered heterocycle;
• R 5 is hydrogen or C 1 -C 4 alkyl. In some embodiments, R 5 is hydrogen.
• W is -NR 3 -.
• R 3 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl. In some embodiments, R 3 is hydrogen.
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is CR 11 ; or X 1 is CR 11 , X 2 is CR 11 , and X 3 is N; or X 1 is CR 11 , X 2 is N, and X 3 is CR 11 ; or X 1 is CR 11 , X 2 is N, and X 3 is N; or X 1 is N, X 2 is CR 11 , and X 3 is CR 11 ; or X 1 is N, X 2 is CR 11 , and X 3 is N; or X 1 is N, X 2 is N, and X 3 is CR 11 .
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is CR 11 ; or X 1 is CR 11 , X 2 is CR 11 , and X 3 is N; or X 1 is CR 11 , X 2 is N, and X 3 is CR 11 ; or X 1 is N, X 2 is CR 11 , and X 3 is CR 11 .
• X 1 is CR 11
• X 2 is CR 11
• X 3 is CR 11 .
• the compound has a structure of Formula (IV):
• the compound has a structure of Formula (VI):
• Formula (VI) or a pharmaceutically acceptable salt, tautomer, or solvate thereof wherein: A 1 and A 2 are each independently N or C; and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• a 1 is C; A 2 is C; A 3 is N; A 4 is NR 8 ; and A 5 is CR 8 ; or A 1 is C; A 2 is C; A 3 is NR 8 ; A 4 is N; and A 5 is CR 8 ; or A 1 is C; A 2 is N; A 3 is N; A 4 is CR 8 ; and A 5 is CR 8 .
• the compound has a structure of Formula (VIa-1):
• the compound has a structure of Formula (VIf-1):
• each R 8 is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, - CO 2 H, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CO 2 H, or -CO 2 CH 3 .
• each R 8 is independently hydrogen, methyl, -CD 3 , -OH, -CH 2 OH, -CF 3 , oxetanyl, -CN, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, -CD 3 , -CH 2 OH, oxetanyl, or -CO 2 CH 3 .
• each R 6 and R 7 is independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl. In some embodiments, each R 6 and R 7 is independently hydrogen, deuterium, F, or methyl.
• Z is -NR 10 -, -0-, or -SO2-. In some embodiments, Z is -NR 10 - or -0-. In some embodiments, Z is -NR 10 -. In some embodiments, R 10 is hydrogen, C 1 -C 4 alkyl, Ci- C4 deuteroalkyl, or cyclopropyl. In some embodiments, Z is -0-.
• R 2 is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• the compound has a structure of Formula (VIII):
• VIII or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: V is N, CH, or CR 13 ; q is 1, 2, or 3; A 1 and A 2 are each independently N or C; and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• V is N.
• V is CH or CR 13 .
• each R 13 is independently -F, -Cl, -CH 3 , or -CF 3 .
• the compound has a structure of Formula (IX):
• Formula (IX) or a pharmaceutically acceptable salt, tautomer, or solvate thereof wherein: A 1 and A 2 are each independently N or C; and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• R 14 is unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4- membered heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, - NH(CH ), -N(CH ) 2 , -CH3, -CH2CH3, -CHF2, -CF3, -0CH3, -0CHF2, and -OCF3.
• B 1 is CR 12a ; and B 2 is CR 12b ; or B 1 is N; and B 2 is CR 12b ; or B 1 is CR 12a ; and B 2 is N; or B 1 is N; and B 2 is N.
• B 1 is CR 12a ; and B 2 is CR 12b ; or B 1 is N; and B 2 is CR 12b .
• R 12a and R 12b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN. In some embodiments, R 12a and R 12b are each hydrogen.
• compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.
• the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
• the pharmaceutical composition is formulated for administration to a mammal by oral administration.
• the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
• the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
• the pharmaceutical composition in the form of an ointment, a lotion, a cream, an oil, a gel, a transdermal patch, or other topical formulation.
• the pharmaceutical composition is in the form of a liquid solution, suspension, gel, depot, or other preparation that can be administered to the eye or surrounding tissue (e.g., eye drops).
• Described herein are compounds of Formula (Al), or a pharmaceutically acceptable salt, tautomer, or solvate thereof useful in the treatment of TYK2-mediated disorders. Described herein are compounds of Formula (Al), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful in the treatment of an inflammatory or autoimmune disease.
• the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
• the disease is selected from psoriasis, psoriatic arthritis, vitiligo, atopic dermatitis, alopecia, and hidradenitis suppurativa.
• the disease is selected from interferonopathies such as, by way of example, Alcardi-Goutieres syndrome.
• the effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
• the mammal is a human.
• compounds provided herein are topically administered to a human.
• Articles of manufacture which include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating TYK2, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating TYK2, are provided.
• TYK2 activation has been linked to many diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.
• TYK2 is associated with respiratory diseases and conditions such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.
• COPD chronic obstructive pulmonary disease
• GCH Goblet cell hyperplasia
• mucous hypersecretion is mediated by IL-13-induced activation of the TYK2/STAT6 pathway.
• TYK2 is also associated with autoimmune diseases and conditions, such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.
• MS multiple sclerosis
• SLE systemic lupus erythematosus
• TYK2 has also been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. These effects are largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.
• Compounds described herein are inhibitors of TYK2.
• compounds described herein are selective for TYK2 over other JAKs.
• compounds described herein bind selectively/ specifically to the pseudokinase domain (JH2) of TYK2.
• a compound described herein binds to an allosteric site of TYK2.
• a compound described herein may be useful in the treatment of TYK2 mediated diseases or disorders.
• R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle;
• B 1 is N or CR 12a ;
• B 2 is N or CR 12b ;
• R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;
• R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle; or R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; or R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5- or 6-membered heterocycle;
• the compound is not 6-(cyclopropanecarboxamido)-4-((2,5- dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3- carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5- fluoropyri din-2 -yl)amino)-N-methylnicotinamide, 4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N- methylnicotinamide, nor 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl)-2H-pyrazolo
• the compound of Formula (I) is not 4-((2,5-dimethyl-4,5- dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N- methylnicotinamide, which has the following structure:
• the compound of Formula (I) is not 4-((2,5-dimethyl-4,5- dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N- methylnicotinamide, which has the following structure:
• the compound of Formula (I) is not 6- (cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-6- yl)amino)-N-methylpyridazine-3-carboxamide, which has the following structure:
• R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl.
• R 1 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl.
• R 1 is hydrogen or C 1 -C 6 alkyl.
• R 1 is hydrogen or C 1 -C 4 alkyl.
• R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl.
• R 1 is hydrogen or methyl.
• R 1 is hydrogen.
• R 1 is methyl.
• R 5 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 5 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 5 is hydrogen or C 1 -C 4 alkyl. In some embodiments, R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 5 is hydrogen or methyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is methyl.
• W is -0-.
• W is -NR 3 -.
• the compound is a compound of Formula (la) or Formula (lb):
• R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3 . In some embodiments, R 4 is -CD 3 .
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , -CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3. In some embodiments, R 4 is -CD 3.
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , -CH 2 D, -CHD 2, or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH 3 . In some embodiments, R 4 is -CD 3 .
• R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 3 and R 4 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 3 is hydrogen; and R 4 is hydrogen, -CH 3 , -CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 3 is hydrogen; and R 4 is hydrogen. In some embodiments, R 3 is hydrogen; and R 4 is C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl. In some embodiments, R 3 is hydrogen; and R 4 is C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 3 is hydrogen; and R 4 is -CH 3 , -CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 3 is hydrogen; and R 4 is -CH 3. In some embodiments, R 3 is hydrogen; and R 4 is -CDs.
• R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. In some embodiments, R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted monocyclic N-containing heterocycloalkyl. In some embodiments, R 3 and R 4 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 3- to 6-membered N-containing heterocycloalkyl.
• the compound is a compound of Formula (II) or Formula (III):
• Formula (II) Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• the compound is a compound of Formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is CR 11 . In some embodiments, X 1 is CR 11 , X 2 is CR 11 , and X 3 is N. In some embodiments, X 1 is CR 11 , X 2 is N, and X 3 is CR 11 . In some embodiments, X 1 is CR 11 , X 2 is N, and X 3 is N. In some embodiments, X 1 is N, X 2 is CR 11 , and X 3 is CR 11 . In some embodiments, X 1 is N, X 2 is CR 11 , and X 3 is N. In some embodiments, X 1 is N, X 2 is N, and X 3 is CR 11 . In some embodiments, X 1 is N, X 2 is CR 11 , and X 3 is N. In some embodiments, X 1 is N, X 2 is N, and X 3 is CR 11 .
• each R 11 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 ) 2.
• each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 ) 2. In some embodiments, each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN. In some embodiments, each R 11 is independently hydrogen, halogen, or -CN. In some embodiments, each R 11 is independently hydrogen or halogen. In some embodiments, each R 11 is independently hydrogen, fluoro, or chloro. In some embodiments, each R 11 is independently hydrogen or fluoro. In some embodiments, each R 11 is hydrogen.
• X 1 is CH, X 2 is CH, and X 3 is CH; or X 1 is CH, X 2 is CH, and X 3 is N; or X 1 is CH, X 2 is N, and X 3 is CH; or X 1 is N, X 2 is CH, and X 3 is CH.
• the compound is a compound of Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3. In some embodiments, R 4 is -CD 3.
• each R 8 is independently hydrogen, methyl, -CD 3 , -OH, -CH 2 OH, -CF 3 , oxetanyl, -CN, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, -CD 3 , -CH 2 OH, oxetanyl, or -CO 2 CH 3 .
• p is 0, 1, or 2.
• p is 1 or 2.
• p is 1.
• p is 2.
• p is 0; and Ring A is therefore unsubstituted.
• Ring A is . In some embodiments, Ring A is a a a embodiments, A ' p is - R . In some embodiments, L (R 8 )P IS ,
• a 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• the compound is a compound of Formula (VI) or Formula (VII):
• Formula (VI) Formula (VII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein A 1 and A 2 are each independently N or C; and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• the compound is a compound of Formula (VI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• the compound is a compound of Formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C1-C2 alkyl, or C1-C2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH3, - CH2D, -CHD2 , or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CFb. In some embodiments, R 4 is -CD3.
• a 1 is C; A 2 is C; A 3 is N; A 4 is NR 8 ; and A 5 is CR 8 ; or A 1 is C; A 2 is C; A 3 is NR 8 ; A 4 is N; and A 5 is CR 8 ; or A 1 is C; A 2 is N; A 3 is N; A 4 is CR 8 ; and A 5 is CR 8 .
• the compound is a compound of Formula (VIa-1):
• the compound of Formula (VIa-1) is not 6- (cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-6-((5-fluoropyri din-2 -yl)amino)-N-methylnicotinamide, nor 4-((2,5- dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4- yl)amino)-N-methylnicotinamide.
• R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C1-C2 alkyl, or C1-C2 deuteroalkyl.
• R 4 is hydrogen, -CH3, - CH2D, -CHD2 , or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CFb. In some embodiments, R 4 is -CD3.
• the compound is a compound of Formula (VIc-1):
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CFb. In some embodiments, R 4 is -CD 3.
• the compound is a compound of Formula (VIf-1):
• the compound of Formula (Vlf-a) is not 6-
• R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3. In some embodiments, R 4 is -CD 3.
• each R 8 is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO 2 H, or - CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CO 2 H, or -CO 2 CH 3.
• each R 8 is independently hydrogen, methyl, -CD 3 , -OH, - CH 2 OH, -CF 3 , oxetanyl, -CN, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, -CD 3 , -CH 2 OH, oxetanyl, or -CO 2 CH 3.
• each R 8 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or Ci- C 4 fluoroalkyl. In some embodiments, each R 8 is independently hydrogen, methyl, ethyl, isopropyl, -CD 3 , or -CF 3. In some embodiments, each R 8 is independently hydrogen, methyl, - CD 3 , or -CF 3. In some embodiments, each R 8 is independently hydrogen or methyl.
• each R 6 and R 7 is independently hydrogen or C 1 -C 4 alkyl. In some embodiments, each R 6 and R 7 is independently hydrogen, deuterium, F, Cl, -CD 3 , or methyl. In some embodiments, each R 6 and R 7 is independently hydrogen, deuterium, F, or methyl. In some embodiments, each R 6 and R 7 is independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, each R 6 and R 7 is hydrogen. In some embodiments, each R 6 and R 7 is deuterium. In some embodiments, each R 6 and R 7 is F.
• n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
• Z is NH, NCH 3 , or NCD 3 . In some embodiments, Z is NCH 3 or NCD 3 . In some embodiments, Z is NCH 3 . In some embodiments, Z is NCD 3 .
• R 2 is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted monocyclic 5-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted
• R 2 is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, or unsubstituted or substituted tetrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, or unsubstituted or substituted pyrazolyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 . .,N
• the compound is a compound of Formula (VIII):
• V is N, CH, or CR 13 ; q is 1, 2, or 3;
• a 1 and A 2 are each independently N or C;
• a 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 ; wherein two adjacent ring atoms selected from A 1 , A 2 , A 3 , A 4 , and A 5 are N or NR 8 ; and the remaining atoms are C or CR 8 .
• the compound is a compound of Formula (VIIIa-1):
• Villa- 1 or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 ; and q is 1, 2, or 3.
• the compound of Formula (VIIIa-1) is not 4-((2,5-dimethyl-4,5- dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N- methylnicotinamide, or 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)- 6-((2,6-dimethylpyrimidin-4-yl)amino)-N-methylnicotinamide.
• each R 13 is independently halogen, C1-C4 alkyl, or Ci-C4fluoroalkyl.
• each R 13 is independently -F, -Cl, -CH3, or -CF3.
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 1 is hydrogen or C1-C4 alkyl. In some embodiments, R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl.
• R 1 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle. In some embodiments, R 1 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycloalkyl. In some embodiments, R 1 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle. In some embodiments, R 1 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- membered monocyclic heterocycloalkyl.
• R 1 is hydrogen
• the compound of Formula (IXa-1) is not 6-
• R 4 is hydrogen, -CH3, - CFhD, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CFb. In some embodiments, R 4 is -CD 3.
• the compound is a compound of Formula (IXc-1):
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3. In some embodiments, R 4 is -CD 3.
• the compound is a compound of Formula (IXf-1):
• the compound of Formula (IXf-1) is not 6-
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3 . In some embodiments, R 4 is -CD 3 .
• R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.
• R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups.
• R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, C 1 -C 6 alkyl, -CN, -OR 18 , and -N(R 18 ) 2 .
• R 14 is methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, .
• R 14 is methyl, -CD 3 , ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, some embodiments, R 14 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,
• B 1 is CR 12a ; and B 2 is CR 12b ; or B 1 is N; and B 2 is CR 12b ; or B 1 is CR 12a ; and B 2 is N; or B 1 is N; and B 2 is N.
• B 1 is CR 12a ; and B 2 is CR 12b .
• B 1 is N; and B 2 is CR 12b .
• B 1 is CR 12a ; and B 2 is N.
• B 1 is N; and B 2 is N.
• B 1 is CR 12a ; and B 2 is CR 12b ; or B 1 is N; and B 2 is CR 12b .
• R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5- or 6-membered heterocycle. In some embodiments, R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5-membered heterocycle. In some embodiments, R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted pyrazolidinone ring. In some embodiments, ,
• the compound is a compound of Formula (XII):
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3 . In some embodiments, R 4 is -CD 3 .
• R 2 is a Ring B that is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted monocyclic 6-membered heteroaryl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• R 2 is a Ring B that is an unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, wherein if Ring B is substituted then Ring B is substituted with q instances of R 13 .
• each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.
• R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle;
• B 1 is N or CR 12a ;
• R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl;
• B 2 is N or CR 12b ;
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, Ci- C 4 fluoroalkyl, or -CN. In some embodiments, each R 11 is independently hydrogen, halogen, or - CN. In some embodiments, each R 11 is independently hydrogen or halogen. In some embodiments, each R 11 is independently hydrogen, fluoro, or chloro. In some embodiments, each R 11 is independently hydrogen or fluoro. In some embodiments, each R 11 is hydrogen. [00168] In some embodiments, the compound of Formula (XV) is a compound of Formula (VIc-1):
• R 4 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2, or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3 . In some embodiments, R 4 is -CD 3 .
• each R 8 is independently hydrogen, methyl, -CD 3 , -OH, -CH 2 OH, -CF 3 , oxetanyl, -CN, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, -CD 3 , -CH 2 OH, oxetanyl, or -CO 2 CH 3 .
• each R 6 and R 7 is independently hydrogen, deuterium, F, Cl, - CD 3 , or methyl.
• each R 6 and R 7 is independently hydrogen, deuterium, F, or methyl.
• each R 6 and R 7 is independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, each R 6 and R 7 is hydrogen. In some embodiments, each R 6 and R 7 is deuterium. In some embodiments, each R 6 and R 7 is F.
• n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
• R 10 is -CH 3 or -CD 3 . In some embodiments, R 10 is - CH 3 . In some embodiments, R 10 is -CD 3 . [00175] In some embodiments, Z is NH, NC3 ⁇ 4, or NCD 3. In some embodiments, Z is NCH 3 or NCD 3. In some embodiments, Z is NCH 3. In some embodiments, Z is NCD 3.
• Z is -0-.
• R 2 is as defined herein.
• the compound is a compound of Formula (XVII):
• R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle;
• B 1 is N or CR 12a ;
• B 2 is N or CR 12b ;
• R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;
• R 15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle
• the compound of Formula (XVII) is not 6- (cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-6-((5-fluoropyri din-2 -yl)amino)-N-methylnicotinamide, nor 4-((2,5- dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4- yl)amino)-N-methylnicotinamide.
• Z is -NR 10 - or -0-;
• R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl;
• X 1 , X 2 , and X 3 are each independently CR 11 orN; each R 11 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, - OH, -OR 17 , or -N(R 16 ) 2 ;
• B 1 is N or CR 12a ;
• R 12a and R 12b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN;
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• the compound of Formula (VIa-1) is not 6- (cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-6-((5-fluoropyri din-2 -yl)amino)-N-methylnicotinamide, nor 4-((2,5- dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4- yl)amino)-N-methylnicotinamide.
• R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C1-C2 alkyl, or C1-C2 deuteroalkyl.
• R 4 is hydrogen, -CH3, - CH2D, -CHD2 , or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CFb. In some embodiments, R 4 is -CD3.
• each R 8 is independently hydrogen, methyl, -CD 3 , -OH, -CH 2 OH, -CF 3 , oxetanyl, -CN, or -CO 2 CH 3 ; wherein if R 8 is attached to a nitrogen atom, then R 8 is hydrogen, methyl, -CD 3 , -CH 2 OH, oxetanyl, or -CO 2 CH 3 .
• each R 6 and R 7 is independently hydrogen, deuterium, F, Cl, - CD 3 , or methyl.
• each R 6 and R 7 is independently hydrogen, deuterium, F, or methyl.
• n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
• Z is NH, NCH 3 , or NCD 3 . In some embodiments, Z is NCH 3 or NCD 3 . In some embodiments, Z is NCH 3 . In some embodiments, Z is NCD 3 .
• Z is -0-.
• R 2 is as defined herein.
• the compound is a compound of Formula (XVIII):
• R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, or monocyclic heterocycle;
• B 1 is N or CR 12a ;
• B 2 is N or CR 12b ;
• R 14 is hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 -C 6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle;
• R 15 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl
• Z is -NR 10 - or -0-;
• R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl;
• X 1 , X 2 , and X 3 are each independently CR 11 orN; each R 11 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, - OH, -OR 17 , or -N(R 16 ) 2 ;
• B 1 is N or CR 12a ;
• B 2 is N or CR 12b ;
• R 12a and R 12b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN;
• R 14 is unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl; wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, -CN, -NH 2 , -OH, -NH(CH ), -N(CH ) 2 , -CH , -CH 2 CH , -CHF 2 , -CF , - OCH , -OCHF 2 , and -OCF ; each R 6 and R 7 is independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; or
• R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or C 1 -C 4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl.
• R 4 is hydrogen, Ci-C 2 alkyl, or Ci-C 2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH 3 , - CH 2 D, -CHD 2 or -CD 3 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is - CH 3 . In some embodiments, R 4 is -CD 3 .
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is CR 11 ; or X 1 is CR 11 , X 2 is CR 11 , and X 3 is N; or X 1 is CR 11 , X 2 is N, and X 3 is CR 11 ; or X 1 is N, X 2 is CR 11 , and X 3 is CR 11 .
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is CR 11 .
• X 1 is CR 11 , X 2 is CR 11 , and X 3 is N.
• X 1 is CR 11 , X 2 is N, and X 3 is CR 11 .
• X 1 is N, X 2 is CR 11 , and X 3 is CR 11 .
• X 1 is N, X 2 is CR 11 , and X 3 is CR 11 .
• each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, Ci- C4 fluoroalkyl, or -CN. In some embodiments, each R 11 is independently hydrogen, halogen, or - CN. In some embodiments, each R 11 is independently hydrogen or halogen. In some embodiments, each R 11 is independently hydrogen, fluoro, or chloro. In some embodiments, each R 11 is independently hydrogen or fluoro. In some embodiments, each R 11 is hydrogen. [00201] In some embodiments, the compound of Formula (XV) is a compound of Formula (VIc-1):
• the compound of Formula (VIf-1) is not 6-
• R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C1-C2 alkyl, or C1-C2 deuteroalkyl.
• n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
• Z is -NR 10 -.
• R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl.
• R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl.
• R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl.
• R 10 is hydrogen, -CH3, or -CD3.
• R 10 is C1-C4 alkyl or C1-C4 deuteroalkyl.
• R 10 is -CH3 or -CD3.
• R 10 is - CH3.
• R 10 is -CD3.
• R 2 is as defined herein.
• B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 are as described herein. In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 are as described in Table 2.
• B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 are as described herein. In some embodiments B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 are as described in Table 3. In some embodiments, the compound is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5- dihydropyrazolo[l,5-a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide. [00216] In some embodiments, compounds described herein have the following structure:
• R 2 , R 4 , and Z are as described herein. In some embodiments R 2 , R 4 , and Z are as described in Table 5.
• provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 2.
• provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 5.
• compounds described herein are in the form of pharmaceutically acceptable salts.
• the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• the solvated forms of the compounds presented herein are also considered to be disclosed herein.
• “Pharmaceutically acceptable,” as used herein refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
• Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G.
• solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
• the compounds of Formula (I) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I) exists in the R configuration. In some embodiments, the compound of Formula (I) exists in the S configuration.
• the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
• the compounds and methods provided herein include all cis, trans, syn, anti,
• E Delta-deltasional (E), and sixteen (Z) isomers as well as the appropriate mixtures thereof.
• stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
• compounds of Formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
• compounds described herein are prepared as prodrugs.
• a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
• An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity.
• Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al .,
• a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like.
• a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
• a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
• compounds described herein are prepared as alkyl ester prodrugs.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I) as set forth herein are included within the scope of the claims.
• some of the herein-described compounds is a prodrug for another derivative or active compound.
• any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety.
• the prodrug moiety is as described above.
• the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
• Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
• heterocyclic rings may exist in tautomeric forms.
• nucleophilic substitution of one chloro group of intermediate A with the free amino group of B affords intermediate C.
• this substitution can be carried out with a suitable Lewis acid such as Zn(OAc)2.
• a suitable base such as LDA.
• intermediate C may be accessed by a cross-coupling reaction of intermediates A and B.
• Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.
• intermediate C is converted to the final compound D (e.g., compound 1) via a cross-coupling reaction.
• Cross-coupling reactions may be organometallic cross-couplings such as Suzuki-Miyaura reactions, Buchwald-Hartwig reactions, Heck reactions, Ullman couplings, Chan-Lam couplings, and the like.
• Ci-C x includes C1-C2, C1-C3 . . . Ci-C x.
• a group designated as "C1-C6" indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
• C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, /.vo-propyl, «-butyl, iso butyl, sec-butyl, and /-butyl.
• an “alkyl” group refers to an aliphatic hydrocarbon group.
• the alkyl group is branched or straight chain.
• the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- Cioalkyl.
• a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
• an alkyl is a C1-C6 alkyl.
• the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
• an “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6 alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-. [00261] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
• alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
• hydroxyalkyl refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl.
• a hydroxyalkyl is a Ci-C4hydroxyalkyl.
• Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like.
• aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by an amino.
• aminoalkyl is a Ci-C4aminoalkyl.
• Typical aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH2CH2CH2NH2, - CH2CH2CH2CH2NH2, and the like.
• alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
• R is H or an alkyl.
• an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
• alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
• an alkenyl group has the formula -CoC-R, wherein R refers to the remaining portions of the alkynyl group.
• R is H or an alkyl.
• an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
• Non-limiting examples of an alkynyl group include -CoCH, -CoCCH3 - OCCH2CH3, -CH 2 CoCH.
• heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g ., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof.
• a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• a heteroalkyl is a Ci-C 6 heteroalkyl.
• aromatic refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer.
• aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
• aryl e.g., phenyl
• heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
• pyridine e.g., pyridine
• the term includes monocyclic or fused-ring polycyclic ( i.e ., rings which share adjacent pairs of carbon atoms) groups.
• Carbocyclic refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• aryl is phenyl or a naphthyl.
• an aryl is a phenyl.
• an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl.
• an aryl is a C 6 -Cioaryl.
• an aryl group is a monoradical or a diradical (i.e., an arylene group).
• cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
• cycloalkyls are spirocyclic or bridged compounds.
• cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]pentyl.
• a cycloalkyl is a C3- C 6 cycloalkyl.
• a cycloalkyl is a C3-C4cycloalkyl.
• halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
• fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
• a fluoroalkyl is a Ci-C 6 fluoroalkyl.
• heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
• Non-aromatic heterocyclic groups also known as heterocycloalkyls
• aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• at least one of the two rings of a bicyclic heterocycle is aromatic.
• both rings of a bicyclic heterocycle are aromatic.
• Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
• Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
• a heteroaryl contains 0-4 N atoms in the ring.
• a heteroaryl contains 1-4 N atoms in the ring.
• a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
• a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
• heteroaryl is a Ci-C9heteroaryl.
• monocyclic heteroaryl is a Ci-Csheteroaryl.
• monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
• bicyclic heteroaryl is a C6-C9heteroaryl.
• a “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl.
• the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2- onyl, or thiazolidin-2-onyl.
• a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
• bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
• moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• modulate means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
• modulator refers to a molecule that interacts with a target either directly or indirectly.
• the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
• a modulator is an antagonist.
• a modulator is an inhibitor.
• co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
• an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
• an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
• An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
• the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
• the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
• An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
• the term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• the term “fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• the term “non-fixed combination” means that the active ingredients, e.g.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
• cocktail therapy e.g. the administration of three or more active ingredients.
• subject or “patient” encompasses mammals.
• mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
• the mammal is a human.
• the terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
• the compounds described herein are formulated into pharmaceutical compositions.
• Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• a summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
• a compound or a pharmaceutical composition of the present disclosure is, in some embodiments, useful for the treatment of a TYK2 mediated disease or disorder.
• the pharmaceutical composition is effective at treating a disease or disorder wherein TYK2 is overexpressed or hyperactive.
• the pharmaceutical composition is effective at treating a disease or disorder which would benefit from a reduction in TYK2 activity or expression.
• the pharmaceutical composition is useful in the treatment of disease or disorder associated with high levels of cytokines driven by TYK2, such as interferons (e.g. IFN-a, IFN-b, IFN-K, IFN-d, IFN-e, IFN-t, IFN-co, and IFN-z (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-1 1, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF.
• the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratory disease or disorder, type 1 diabetes, and interferonopathies such as Alcardi-Goutieres syndrome, or combinations thereof.
• the pharmaceutical composition is useful in the treatment of an inflammatory disease or disorder.
• the inflammatory disease or disorder is an auto-inflammatory disease or disorder, a host-mediated inflammatory disease or disorder, an injury -related inflammatory disease or disorder, an infection-related inflammatory disease or disorder, a hyperproliferative (e.g., cancer, fibrosis) mediated inflammatory disease or disorder.
• the inflammatory disease or disorder or infection-related inflammatory disease or disorder is a respiratory disease or disorder.
• the respiratory disease or disorder is associated with a viral in microbial infection.
• the respiratory disease or disorder is a problematic immune response to a viral or microbial infection.
• the respiratory disease or disorder is associated with a coronavirus such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2.
• the pharmaceutical composition is effective in decreasing symptoms associated with COVID-19, or an immune response associated therewith.
• an autoimmune disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, Bechet’s disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
• an autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, an autoimmune disease or disorder is psoriasis. In some embodiments, an autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, an autoimmune disease or disorder is dry eye or uveitis. In some embodiments, an autoimmune disease or disorder is Crohn’s disease. In some embodiments, an autoimmune disease or disorder is atopic dermatitis.
• IBS irritable bowel disease
• IBS-D irritable bowel disease with diarrhea
• an autoimmune disease or disorder is dry eye or uveitis. In some embodiments, an autoimmune disease or disorder is Crohn’s disease. In some embodiments, an autoimmune disease or disorder is atopic dermatitis.
• enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
• parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
• compounds described herein can be administered locally to the area in need of treatment, by for example, topical application such as creams or ointments. Additional examples of local administration of the present compounds include eye drops, ocular creams, gels or hydrogels, implants, transdermal patches, or drug depots.
• a pharmaceutical composition is administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, dry powder spray).
• compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient is presented as a bolus, electuary or paste.
• compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions may be presented in unit-dose or multi dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
• sterile liquid carrier for example, saline or sterile pyrogen-free water
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously).
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions may be administered topically, that is by non-systemic administration.
• non-systemic administration includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the installation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
• systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
• compositions suitable for topical administration include liquid or semi liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
• compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
• Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
• the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of TYK2 activity.
• Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
• compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
• Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
• prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• a maintenance dose is administered if necessary.
• the dosage or the frequency of administration, or both is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g ., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day.
• the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight.
• the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
• the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
• Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50.
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
• the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
• the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity.
• the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
• the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non- systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours;
• the compound is administered to the mammal every 24 hours.
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 2 days to 1 year.
• the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (z.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
• an adjuvant z.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
• the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
• a compound described herein, or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
• the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
• dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
• the compound provided herein when co administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
• the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
• the compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
• the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
• the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
• a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
• the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
• TYK non-receptor tyrosine-protein kinase [00326] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
• Step-1 3-bromo-2-(prop-2-yn-l-yloxy)benzaldehyde (I-lb): To a stirred solution of 3-bromo-2-hydroxybenzaldehyde I-la (10.0 g, 49.7 mmol) in DMF (50.0 mL) was added anhydrous K 2 CO 3 (20.6 g, 149 mmol) at 0 °C and stirred for 10 min. To this was then added propargyl bromide (7.54 mL, 99.5 mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC.
• Step-2 6-bromo-2,4-dihydrochromeno[4,3-c]pyrazole (I-lc): To a stirred solution of I-lb (11.3 g, 47.3 mmol) in MeOH (25.0 mL) and water (25.0 mL) was added KOtBu (8.03 g, 70.9 mmol) and /Mol uenesul fony 1 hy drazi de (17.6 g, 93.8 mmol) at room temperature. The reaction mixture was then stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was cooled to room temperature and water (250 mL) was added to it.
• Step-3 6-bromo-2-methyl-2,4-dihydrochromeno[4,3-c] pyrazole (I-ld) and 6- bromo-l-methyl-l,4-dihydrochromeno[4,3-c]pyrazole (1-le): To a solution of I-lc (4.00 g, 15.9 mmol) in DMF (60.0 mL) was added CS2CO3 (10.4 g, 31.9 mmol) under nitrogen atmosphere and stirred for 30 min. To this was then added Mel (1.20 mL, 19.1 mmol) and the reaction mixture was stirred at 80 °C for 16 h in a sealed tube. The progress of the reaction was monitored by TLC.
• Step-4 tert-butyl (2-methyl-2,4-dihydrochromeno[4,3-c] pyrazol-6-yl)carbamate (I-lf): Argon gas was purged through a stirred suspension of I-ld (3.40 g, 12.8 mmol), tert- butyl carbamate (2.25 g, 19.2 mmol) and CS2CO3 (8.36 g, 25.6 mmol) in 1,4-dioxane (20.00 mL) for 15 min.
• Step-5 2-methyl-2,4-dihydrochromeno[4,3-c] pyrazol-6-amine (1-1): To a stirred solution of I-lf (2.30 g, 7.63 mmol) in DCM (40.0 mL) was added trifluoroacetic acid (10.0 mL) at 0 °C under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature over 2 h. The progress of the reaction was monitored by TLC. After completion, volatiles were removed under reduced pressure and saturated NaHCCh solution (50 mL) was added to the residue.
• Step-1 tert-butyl (l-methyl-l,4-dihydrochromeno[4,3-c]pyrazol-6-yl)carbamate (I-2a): I-2a (0.8 g) was synthesized by following experimental procedure described for the synthesis of 1-1 (step-4) using I-le (1.4 g, 5.28 mmol) as the starting material. LCMS (ES) m/z; 302.1 [M+H] + .
• Step-2 l-methyl-l,4-dihydrochromeno[4,3-c]pyrazol-6-amine (1-2): 1-2 (0.4 g) was synthesized by following experimental procedure described for the synthesis of 1-1 using I-2a (0.8 g, 2.65 mmol) as the starting material.
• Step-1 6-bromo-2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole (I-3a): To a stirred solution of I-lc (2.20 g, 8.76 mmol) in DMF (20.0 mL) was added CS2CO3 (5.71 g, 17.5 mmol) and 3-bromooxetane (2.40 g, 17.5 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was then stirred at 80 °C for 16 h in a sealed tube. The progress of the reaction was monitored by TLC.
• Step-2 tert-butyl (2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazol-6- yl)carbamate (I-3b): I-3b (0.92 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-3a (1.7 g, 5.53 mmol) as the starting material. LCMS (ES) m/z 344.0 [M+H] + .
• Step-3 2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazol-6-amine (1-3): 1-3
• Step-1 but-3-yn-2-yl 4-methylbenzenesulfonate (I-4b): To a solution of N,N- dimethylpyridin-4-amine (261 mg, 0.03 eq., 2.14 mmol) in DCM (50 mL) were successively added aqueous but-3-yn-2-ol (5.59 mL, 71.3 mmol), aqueous sodium hydroxide (12.5 mL) and 4-methylbenzene-l-sulfonyl chloride (13.6 g, 71.3 mmol) at 0 °C and then the mixture was stirred at room temperature for 2 h.
• Step-2 3-bromo-2-(but-3-yn-2-yloxy)benzaldehyde (I-4c): To a stirred solution of I- la (5.0 g, 24.9 mmol) in ACN (30 mL) was added anhydrous K2CO3 (5.16 g, 37.3 mmol) and I- 4b (7.25 g, 36.1 mmol) at room temperature. The reaction mixture was then stirred at 90 °C for 3 h. After completion (as indicated by TLC), volatiles were removed under reduced pressure and water (100 mL) was added to the residue.
• Step-3 6-bromo-4-methyl-2,4-dihydrochromeno[4,3-c]pyrazole (I-4d): I-4d (2.62 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-2) using I- 4c (2.5 g, 9.88 mmol) as the starting material. LCMS (ES) m/z 264.8 [M+H] + .
• Step-4 6-bromo-2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole (I-14e) and 6- bromo-l,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazole (I-4f):
• I-4e and I-4f 1.1 g was synthesized by following procedure as described for the synthesis of 1-1 (step-3) using I-4d (2.62 g, 9.88 mmol) as the starting material.
• LCMS (ES) m/z 279.0 [M+H] + .
• Step-5 tert-butyl (2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazol-6- yl)carbamate (I-4g) and tert-butyl (l,4-dimethyl-l,4-dihydrochromeno[4,3-c]pyrazol-6- yl)carbamate (I-4h): I-4g (0.42 g) and I-4h (0.28 g) were synthesized by following procedure as described for the synthesis of 1-1 (step-4) using a mixture of I-4e and I-4f (1.1 g, 3.94 mmol) as the starting material. LCMS (ES) m/z; 316.2 [M+H] + .
• Step-6 2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazol-6-amine (1-4): 1-4 (0.21 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-5) using I- 4g (0.42 g, 1.33 mmol) as the starting material.
• Step-1 Methyl 3-bromo-2-(methylamino)benzoate (I-5b): To a stirred solution of methyl 3-bromo-2-fluorobenzoate I-5a (5.0 g, 21.5 mmol) in 1,4-dioxane (20 mL) was added potassium carbonate (5.93 g, 42.9 mmol) and a solution of 2M MeNFL in THF (21.5 mL, 42.9 mmol) at room temperature. The reaction mixture was then stirred at 40 °C in a sealed tube for 16 h, while monitoring progress by LCMS. After completion, volatiles were removed under reduced pressure and the residue was partitioned between DCM (100 mL) and water (50 mL).
• Step-2 (3-bromo-2-(methylamino)phenyl)methanol (I-5c): To a stirred solution of I-5b (9.50 g, 38.9 mmol) in anhydrous DCM (100 mL) was added a 1M solution of DIBAL-H (117 mL, 117 mmol) drop wise at 0 °C. The reaction mixture was then allowed to warm to room temperature over 4 h, while monitoring reaction progress by TLC. After completion, it was cooled to 0 °C and quenched slowly with addition of 10% aqueous solution of citric acid (30 mL).
• Step-3 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (I-5d):
• Step-4 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(prop-2-yn- l-yl)aniline (I-5e): To a stirred solution of I-5d (6.50 g, 19.7 mmol) in ACN (65 mL) was added anhydrous K2CO3 (8.16 g, 59.0 mmol) and propargyl bromide (4.47 mL, 59.0 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 24 h, while monitoring reaction progress by TLC.
• Step-5 (3-bromo-2-(methyl(prop-2-yn-l-yl)amino)phenyl)methanol (I-5f): 1M solution of TBAF in THF (22.8 mL, 22.8 mmol) was added to a stirred solution of I-5e (7.00 g, 19.0 mmol) in THF (70 mL) at 0 °C and the reaction mixture was stirred for 30 min. After complete consumption of starting material (as indicated by TLC), saturated NH4CI solution (50 mL) was added to it and extraction was carried out using EtOAc (70 mL x 2).
• Step-6 3-bromo-2-(methyl(prop-2-yn-l-yl)amino)benzaldehyde (I-5g): To a stirred solution of I-5f (4.50 g, 17.7 mmol) in DCM (50.0 mL) was added DMP (11.3 g, 26.6 mmol) at 0 °C and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction progress was monitored by LCMS. After completion, it was filtered through Celite bed and washed with DCM (20 mL x 2).
• Step-7 6-bromo-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-5h): To a stirred solution of I-5g (3.60 g, 14.3 mmol) in MeOH (20.0 mL) and water (20.0 mL) was added KOtBu (2.75 g, 24.3 mmol) and / oluenesulfonylhydrazide (3.99 g, 21.4 mmol) sequentially at room temperature. The reaction mixture was stirred at 70 °C for 16 h, while monitoring reaction progress by TLC.
• Step-8 6-bromo-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-5i) & 6-bromo-l,5-dimethyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinolone (I-5j): To a stirred solution of I-5h (5.00 g, 18.9 mmol) in DMF (60.0 mL) was added CS2CO3 (12.3 g, 37.9 mmol) and iodomethane (1.42 mL, 22.7 mmol). The reaction mixture was then stirred at 80 °C for 16 h in a sealed tube.
• Step-9 tert-butyl (2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)carbamate (I-llk) and tert-butyl (l,5-dimethyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinolin- 6-yl)carbamate (1-51): Argon gas was purged through a stirred suspension of (I-5i + I-5j) (4.00 g, 14.4 mmol), tert-butyl carbamate (2.53 g, 21.6 mmol) and CS2CO3 (9.37 g, 28.8 mmol) in 1,4- dioxane (50.0 mL) for 15 min.
• Step-10 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-amine (1-5): To a stirred solution of I-5k (1.00 g, 3.18 mmol) in DCM (10.0 mL) was added a 4M solution HC1 in 1,4-dioxane (5.00 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and saturated sodium bicarbonate solution (30 mL) was added to the residue.
• Step-1 l,5-dimethyl-4,5-dihydro-lH-pyrazolo[4,3-c]quinolin-6-amine (1-6): To a stirred solution of 1-51 (contaminated with I-5k) (0.8 g, 2.54 mmol) in DCM (10.0 mL) was added a 4M solution of HC1 in 1,4-dioxane (5.00 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and saturated NaHCCb solution (20 mL) was added to the residue.
• Step-1 6-bromo-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3- c]quinolone (I-7a) and 6-bromo-5-methyl-l-(methyl-d3)-4,5-dihydro-lH-pyrazolo[4,3- c]quinolone (I-7b): I-7a (4.0 g) and I-7b (1.5 g) were synthesized by following procedure as described for the synthesis of 1-5 (step-8) using I-5h (6.0 g, 22.7 mmol) as the starting material. LCMS (ES) m/z; 281.0 [M+H] + .
• Step-2 tert-butyl (5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)carbamate (I-7c): I-7c (3.0 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-7a (3.5 g, 12.4 mmol) as the starting material. LCMS (ES) m/z 318.0 [M+H] + .
• Step-3 5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-amine (1-7): 1-7 (1.1 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-10) using I-7c (3.0 g, 9.45 mmol) as the starting material. LCMS (ES) m/z 218.2 [M+H] + .
• Step-1 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde (I-8b): To a stirred solution of I-8a (10.0 g, 6.21 mmol) in DMF (30.0 mL) was slowly added POCh (30.0 mL) at 0 °C.
• Step-2-3 tert-butyl ((3-bromo-l-methyl-lH-pyrazol-4-yl)methyl)(methyl- d3)carbamate (I-8d): To a stirred solution of I-8b (5.0 g, 26.5 mmol) in MeOH (50 mL) were added TEA (7.37 mL, 52.9 mmol) and methyl-d3 -amine hydrochloride (3.73 g, 52.9 mmol) at 0 °C . The reaction mixture was stirred for 16 h at room temperature before it was cooled to 0 °C.
• Step-4 tert-butyl ((3-(2-fluoro-3-nitrophenyl)-l-methyl-lH-pyrazol-4- yl)methyl)(methyl-d3)carbamate (I-8e): Argon gas was purged through a stirred suspension of I-8d (2.5 g, 8.14 mmol), 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.26 g, 12.2 mmol) and KF (1.42 g, 24.4 mmol) in THF (40.0 mL) for 15 min.
• Step-5 2-methyl-5-(methyl-d3)-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-8f): To a stirred solution of I-8e (2.3 g, 6.26 mmol) in DCM (30.0 mL) was added trifluoroacetic acid (15.0 mL) at 0 °C under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature over 2 h. The progress of the reaction was monitored by TLC. After completion, volatiles were removed under reduced pressure and saturated NaHCCb solution (50 mL) was added to the residue.
• Step-6 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-amine (1-8): To a stirred solution of I-8f (1.4 g, 5.66 mmol) in methanol (20.0 mL) was added 10% Pd/C (241 mg) at room temperature. It was then allowed to stir under hydrogen atmosphere (Eh balloon) for 2 h. After completion, the reaction mixture was filtered through celite bed and washed with methanol (20 mL x 2). The combined filtrate was concentrated under reduced pressure.
• Example 9 Preparation of 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3- c] [l,7]naphthyridin-6-amine (1-9): [00362] Step-1: tert-butyl ((3-(2-chloro-3-fluoropyridin-4-yl)-l-methyl-lH-pyrazol-4- yl)methyl)(methyl-d3)carbamate (I-9a): Argon gas was purged through a solution of I-8d (2.5 g, 8.14 mmol), (2-chloro-3-fluoropyridin-4-yl)boronic acid (3.57 g, 20.3 mmol) and CsF (3.71 g, 24.4 mmol) in THF (30 mL) for 15 min.
• I-8d 2.5 g, 8.14 mmol
• (2-chloro-3-fluoropyridin-4-yl)boronic acid (3.57
• Step-2 6-chloro-2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridine (I-9b): A 4M solution of HC1 in 1,4-dioxane (50 mL) was added to I-9a (1.9 g, 5.31 mmol) and stirred at room temperature for 16 h. After completion, volatiles were removed under reduced pressure and dried (co-evaporation with 1,4-dioxane).
• Step-3 N-(2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-9c): Argon gas was purged through a stirred suspension of I-9b (1 g, 4.21 mmol), cyclopropanecarboxamide (0.72 g, 8.41 mmol) and CS2CO3 (4.11 g, 12.6 mmol) in 1,4-dioxane (20 mL) for 15 min.
• Step-4 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin- 6-amine (1-9): To a stirred solution of I-9c (0.7 g, 2.44 mmol) in THF (10 mL) was added LiOH (0.29 g, 12.2 mmol) in water (5.0 mL) at room temperature. It was then stirred at 50 °C for 16 h. After completion, the reaction was diluted with water (20 mL) and extracted with 10% MeOH in DCM (50 mL x 2).
• Step-1-2 tert-butyl ((3-bromo-l-methyl-lH-pyrazol-4- yl)methyl)(methyl)carbamate (I-10b): I-10b (5.7 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-2-3) using I-8b (5.7 g, 30.2 mmol) and methyl amine hydrochloride (6.11 g, 30.2 mmol) as the starting materials. LCMS (ES) m/z; 304.0 [M+H] + .
• Step-3 tert-butyl ((3-(2-chloro-3-fluoropyridin-4-yl)-l-methyl-lH-pyrazol-4- yl)methyl)(methyl)carbamate (I-10c):
• I-10c (4.8 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-1) using I-10b (5.7 g, 18.7 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (8.7 g, 18.7 mmol) as the starting materials.
• LCMS (ES) m/z 355.1 [M+H] + .
• Step-4 6-chloro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridine (I-10d): I-10d (2.8 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-2) using I-10c (4.8 g, 13.5 mmol) as the starting material. LCMS (ES) m/z 235.1 [M+H] + .
• Step-5 N-(2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-6- yl)cyclopropanecarboxamide (I-10e): I-10e (1.5 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-3) using I-10d (1.5 g, 6.39 mmol) and cyclopropanecarboxamide (1.09 g, 12.8 mmol) as the starting materials. LCMS (ES) m/z 284.2 [M+H] + .
• Step-6 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][l,7]naphthyridin-6-amine (I- 10): 1-10 (1.2 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-4) using I-10e (2.0 g, 7.06 mmol) as the starting material.
• LCMS (ES) m/z 216.2 [M+H] + .
• Step-1 ethyl 3-bromo-l-methyl-lH-pyrazole-4-carboxylate (I-llb): To a solution of I-lla (6.5 g, 29.7 mmol) in THF (60 mL) was added sodium hydride (1.78 g fashion 44.5 mmol) portion-wise at 0 °C and stirred for 30 min. To this was then added iodomethane (8.31 mL, 134 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After completion, ice cold water (50 mL) was added to it and extracted with EtOAc (70 mL x 3).
• Step-2 3-bromo-l-methyl-lH-pyrazole-4-carboxylic acid (I-llc): To a solution of I-llb (5 g, 21.5 mmol) in MeOH (30 mL) was added an aqueous solution of NaOH (4.29 g, 107 mmol, in 15 mL water) and resulting mixture was stirred at 85 °C for 1 h. After completion, volatiles were removed under reduced pressure and the aqueous layer was acidified with 5N aqueous HC1 to pH 4.
• Step-3 3-bromo-N-methoxy-N,l-dimethyl-lH-pyrazole-4-carboxamide (I-lld):
• Step-4 3-bromo-l-methyl-lH-pyrazole-4-carbaldehyde-d (I-lle): To a stirred solution of I-lld (10 g, 40.3 mmol) in anhydrous THF (100 mL) was added LiAlD 4 (1.69 g, 40.3 mmol) portion-wise at -78 °C and the reaction mixture was allowed to warm to 0 °C over 1 h. After completion, saturated NH4CI solution (20 mL) was added to it and extraction was carried out using EtOAc (50 mL x 3).
• Step-5 l-(3-bromo-l-methyl-lH-pyrazol-4-yl)-N-methylmethan-d2-amine (I-llf):
• Step-6 tert-butyl ((3-bromo-l-methyl-lH-pyrazol-4-yl)methyl- d2)(methyl)carbamate (I-llg): I-llg (7.5 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-3). LCMS (ES) /z; 306.0 [M+H] + .
• Step-7 tert-butyl ((3-(2-fluoro-3-nitrophenyl)-l-methyl-lH-pyrazol-4-yl)methyl- d2)(methyl)carbamate (I-llh):
• I-llh (1.0 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-4) using I-llg (1.1 g, 3.59 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.44 g, 5.39 mmol) as the starting materials.
• Step-8 2,5-dimethyl-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-4,4-d2 (I- lli): I-lli (0.66 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-5) using I-llh (1.1 g, 3 mmol) as the starting material. LCMS (ES) m/z 247.1 [M+H] + .
• Step-9 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-4,4-d2-6-amine (I- 11): 1-11 (0.5 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-6) using I-lli (0.66 g, 2.68 mmol) as the starting material. LCMS (ES) m/z 217.0 [M+H] + .
• Step-1 tert-butyl ((3-(2-chloro-3-fluoropyridin-4-yl)-l-methyl-lH-pyrazol-4- yl)methyl-d2)(methyl)carbamate (I-12a):
• I-12a (3.8 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-1) using I-llg (4.5 g, 14.7 mmol) and (2- chloro-3-fluoropyridin-4-yl)boronic acid (6.44 g, 36.7 mmol) as the starting materials.
• Step-2 6-chloro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridine-
• I-12b (0.6 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-2) using I-12a (2.0 g, 5.61 mmol) as the starting material.
• Step-3 N-(2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-6-yl-
• I-12c (0.4 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-3) using I-12b (0.63 g, 2.06 mmol) and cyclopropanecarboxamide (1.73 g, 5.32 mmol) as the starting materials.
• LCMS (ES) m/z 286.2 [M+H] + .
• Step-4 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-4,4-d2-6- amine (1-12): 1-12 (0.28 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-4) using I-12c (0.63 g, 2.21 mmol) as the starting material.
• LCMS (ES) m/z; 218.0 [M+H] + .
• Step-1 6-bromo-5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3- c]quinolone (I-13a): I-13a (0.6 g) was synthesized by following procedure as described for the synthesis of 1-3 (step-1) using I-5h (1.35 g, 5.11 mmol) and 3-bromooxetane (0.85 mL, 10.2 mmol) as the starting materials. LCMS (ES) m/z; 320.1 [M+H] + .
• Step-2 tert-butyl (5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)carbamate (I-13b): I-13b (0.5 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-13a (0.6 g, 1.87 mmol) as the starting material. LCMS (ES) m/z; 357.1 [M+H] + .
• Step-3 5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-amine (1-13): 1-13 (0.2 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-5) using I-13b (0.5 g, 1.4 mmol) as the starting material.
• LCMS (ES) m/z; 257.0 [M+H] + .
• Step-1 l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethan-l-ol (I-14a): To a stirred solution of I-8b (25 g, 132.3 mmol) in anhydrous THF (250 mL) was added a 1M solution of MeMgBr in Et 2 0 (198.3 mL, 198.4 mmol) at -78 °C and the reaction mixture was allowed to warm to room temperature over 20 min. After complete consumption of starting material, it was quenched with addition of saturated NH4CI solution (100 mL) and extraction was carried out using EtOAc (70 mL x 3).
• Step-2 l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethan-l-one (I-14b): I-14b (15.5 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-6) using I- 14a (23 g, 122.0 mmol) as the starting material. LCMS (ES) m/z; 203.0 [M+H] + .
• Step-3 l-(3-bromo-l-methyl-lH-pyrazol-4-yl)-N-methylethan-l-amine (I-14c): To a stirred solution of I-14b (15.5 g, 76.35 mmol) in THF (150 mL) was added titanium(IV) isopropoxide (45.2 mL, 152.70 mmol) in a sealed tube at 0 °C. To this then added 2M solution of MeNH2 in THF (76.3 mL, 152.70 mmol) and the reaction mixture was stirred at 60 °C for 16 h. It was then cooled to room temperature and volatiles were removed under reduced pressure.
• Step-4 tert-butyl (l-(3-bromo-l-methyl-lH-pyrazol-4-yl)ethyl)(methyl)carbamate (I-14d): I-14d (19 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-3). LCMS (ES) m/z; 318.0 [M+H] + .
• Step-5 tert-butyl (l-(3-(2-fluoro-3-nitrophenyl)-l-methyl-lH-pyrazol-4- yl)ethyl)(methyl)carbamate (I-14e):
• I-14e (6.0 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-4) using I-14d (5.5 g, 17.3 mmol) and 2-(2-fluoro-3- nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.92 g, 25.9 mmol) as the starting materials.
• LCMS (ES) m/z 379.0 [M+H] + .
• Step-6 2,4,5-trimethyl-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (I-14f): I-
• Step-7 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-amine (1-14): I- 14 (2.2 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-6) using I-14f (3.0 g, 11.6 mmol) as the starting material. LCMS (ES) m/z; 229.2 [M+H] + . 3 ⁇ 4
• Step-1 tert-butyl (l-(3-(2-chloro-3-fluoropyridin-4-yl)-l-methyl-lH-pyrazol-4- yl)ethyl)(methyl)carbamate (I-15a):
• I-15a (3.0 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-1) using I-14d (5.0 g, 15.7 mmol) and (2-chloro-3- fluoropyridin-4-yl)boronic acid (4.13 g, 23.6 mmol) as the starting materials.
• LCMS (ES) m/z 369.1 [M+H] + .
• Step-2 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridine (I-15b): I-15b (5.0 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-2) using I-15a (12.0 g, 32.5 mmol) as the starting material. LCMS (ES) m/z 249.1 [M+H] + .
• Step-3 N-(2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-6- yl)cyclopropanecarboxamide (I-15c): I-15c (0.6 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-3) using I-15b (1.0 g, 4.02 mmol) and cyclopropanecarboxamide (0.68 g, 8.04 mmol) as the starting materials. LCMS (ES) m/z 298.0 [M+H] + .
• Step-4 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c] [l,7]naphthyridin-6-amine (1-15): 1-15 (2.1 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-4) using I-15c (3.36 g, 11.3 mmol) as the starting material. LCMS (ES) m/z 230.1 [M+H] + .
• Racemate 1-15 (2.1 g) was resolved by chiral HPLC separation [Column: CHIRALPAK IC (250 mm x 30 mm x 5 pm); Mobile phase: n-Hexane:IPA with 0.1% DEA (80:20); Flow rate: 40 mL/min)] to afford two enantiomers (I-15A (0.6 g) and I-15B (0.6 g) ⁇ ; peak-1; R t ; 12.06 min and I-15B (0.6 g): peak-2; R t ; 16.23 min ⁇ , which were used further without their absolute configuration determination.
• Step-1 ethyl l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazole-5-carboxylate (I- 16a): To a stirred solution of (3-bromo-2-fluorophenyl)hydrazine (8.0 g, 39.0 mmol) in AcOH (60 mL) was added I-16a (6.06 mL, 49.9 mmol) at room temperature. The reaction mixture was then stirred at 100 °C for 4 h. After completion, volatiles were evaporated under reduced pressure and saturated NaHC0 3 solution (50 mL) was added to the residue.
• Step-3 l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazole-5-carbaldehyde (I- 16d): I-16d (2.5 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-6) using I-16c (3.0 g, 10.12 mmol) as the starting material. LCMS (ES) m/z; 283.0 [M+H] + .
• Step-4 l-(l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazol-5-yl)-N- methylmethanamine (I-16e):
• I-16e (2.2 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-2) using I-16d (2.5 g, 9.18 mmol) and methyl amine hydrochloride (0.86 g mg, 12.7 mmol) as the starting materials.
• Step-5 6-bromo-2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxaline (1-161): To a stirred solution of I-16e (2.2 g, 9.39 mmol) in 1,4-dioxane (10 mL) was added DIPEA (3.1 mL, 18.1 mmol) and the reaction mixture was stirred at 80 °C for 6 h. After completion, it was cooled to room temperature and volatiles were removed under reduced pressure. Water (50 mL) was added to the residue and extraction was carried out using EtOAc (2 x 50 mL).
• Step-6 tert-butyl (2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-6- yl)carbamate (I-16g): I-16g (0.8 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-16f (2.0 g, 8.01 mmol) as the starting material. LCMS (ES) m/z 315.4 [M+H] + .
• Step-7 2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-6-amine (1-16): 1-16
• Step-1 l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazole-5-carboxylic acid (I- 17a): I-17a (4.0 g) was synthesized by following procedure as described for the synthesis of I- 11 (step-2) using I-16b (4.5 g, 13.8 mmol) as the starting material. LCMS (ES) m/z 299.0 [M+H] + .
• Step-2 l-(3-bromo-2-fluorophenyl)-N-methoxy-N,3-dimethyl-lH-pyrazole-5- carboxamide (I-17b): I-17b (3.5 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-3) using I-17a (3.5 g, 11.7 mmol) as the starting material. LCMS (ES) m/z 342.1 [M+H] + .
• Step-3 l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazole-5-carbaldehyde-d (I- 17c): I-17c (2.8 g) was synthesized by following procedure as described for the synthesis of I- 11 (step-4) using I-17b (3.5 g, 10.2 mmol) as the starting material. LCMS (ES) m/z 284.0 [M+H] + .
• Step-4 l-(l-(3-bromo-2-fluorophenyl)-3-methyl-lH-pyrazol-5-yl)-N- methylmethan-d2-amine (I-17d): I-17d (1.5 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-5) using I-17c (3 g, 10.6 mmol) as the starting material. LCMS (ES) m/z 300.1 [M+H] + .
• Step-5 6-bromo-2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxaline-4,4-d2 (I- 17e): I-17e (1.5 g) was synthesized by following procedure as described for the synthesis of I- 16 (step-5) using I-17d (2.2 g, 7.33 mmol) as the starting material. LCMS (ES) m/z; 279.9 [M+H] + .
• Step-6 tert-butyl (2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-6-yl-4,4- d2)carbamate (1-171): I-17f (1.2 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-17e (1.0 g, 3.57 mmol) as the starting material. LCMS (ES) m/z; 317.2 [M+H] + .
• Step-7 2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-4,4-d2-6-amine (1-17): 1-17 (1.1 g) was synthesized by following procedure as described for the synthesis of 1-1 (step- 5) using I-17f (1.5 g, 4.74 mmol) as the starting material. LCMS (ES) m/z 217.2 [M+H] + .
• Step-1 ethyl l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazole-5- carboxylate (I-18a):
• I-18a (6.0 g) was synthesized by following procedure as described for the synthesis of 1-16 (step-1) using I-16a (7.5 mL, 50.3 mmol) and 3-bromo-2-chloro-4- hydrazineylpyridine (12.5 g, 56.2 mmol) as the starting materials.
• Step-2 (l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazol-5-yl)methanol (I- 18c): I-18c (1.9 g) was synthesized by following procedure as described for the synthesis of I- 16 (step-2) using I-18a (3.0 g, 8.71 mmol) as the starting materials. LCMS (ES) m/z; 302.2 [M+H] + .
• Step-3 l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazole-5-carbaldehyde (I-38d): I-18d (3.2 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-6) using I-18c (3.4 g, 11.24 mmol) as the starting material. LCMS (ES) m/z; 300.5 [M+H] + .
• Step-4 l-(l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazol-5-yl)-N- methylmethanamine (I-18e):
• I-18e (3.0 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-2) using I-18d (3.0 g, 9.98 mmol) and methyl amine hydrochloride (2.02 g, 29.9 mmol) as the starting materials.
• LCMS (ES) m/z 314.9 [M+H] + LCMS (ES) m/z 314.9 [M+H] + .
• Step-5 6-chloro-2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]pyrido[3,4-e]pyrazine (I- 181): Argon gas was purged through a stirred suspension of I-18e (1.0 g, 3.17 mmol) and CsOAc (1.22 g, 6.34 mmol) in DMSO (10 mL) for 15 min. To this was then added copper powder (20.1 mg, 0.317 mmol) at room temperature and the reaction mixture was then stirred at 100 °C for 16 h in a sealed tube. It was then cooled to room temperature and saturated NaHCCh solution (30 mL) was added to it.
• Step-6 N-(2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]pyrido[3,4-e]pyrazin-6- yl)cyclopropanecarboxamide (I-18g): I-18g (0.7 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-3) using I-18f (1.7 g 7.63 mmol) as the starting material. LCMS (ES) m/z 284.3 [M+H] + .
• Step-7 2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]pyrido[3,4-e]pyrazin-6-amine (I- 18): 1-18 (0.4 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-4) using I-18g (0.7 g, 2.47 mmol) as the starting material.
• Step-1 l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazole-5-carboxylic acid (I-19a): I-19a (6.5 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-2) using I-18a (12.0 g, 51.03 mmol) as the starting material. LCMS (ES) m/z 316.4 [M+H] + .
• Step-2 (l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazol-5-yl)methan-d2- ol (I-19b): To stirred solution of I-19a (6.0 g, 17.4 mmol) in THF (50 mL) were added TEA (7.33 mL, 52.1 mmol) and isobutyl chloroformate (5.65 mL, 43.4 mmol) at 0 °C. It was then allowed to stir for 30 min.
• reaction mixture was filtered through celite bed and the resulting filtrate was then added drop wise to a solution of NaBD4 (1.2 g, 26.1 mmol) in water (5 ml) at 0 °C.
• the reaction mixture was then allowed to stir at room temperature for 1 h.
• saturated NH 4 CI solution 50 mL was added to it and extraction was carried out using EtOAc (70 mL x 3).
• EtOAc 70 mL x 3
• the combined organic extracts were washed with brine (50 mL), dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure.
• Step-3 l-(2-bromo-3-fluoropyridin-4-yl)-3-methyl-lH-pyrazole-5-carbaldehyde-d (I-19c): I-19c (1.4 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-6) using I-19b (2.3 g, 7.55 mmol) as the starting material. LCMS (ES) m/z; 285.1 [M+H] + .
• Step-4 l-(l-(3-bromo-2-chloropyridin-4-yl)-3-methyl-lH-pyrazol-5-yl)-N- methylmethan-d2-amine (I-19d): I-19d (1.2 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-5) using I-19c (1.1 g, 3.65 mmol) as the starting material. LCMS (ES) m/z; 317.1 [M+H] + .
• Step-5 6-chloro-2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]pyrido[3,4-e]pyrazine- 4,4-d2 (I-19e): I-19e (2.0 g) was synthesized by following procedure as described for the synthesis of 1-18 (step-5) using I-19d (2.6 g, 8.19 mmol) as the starting material. LCMS (ES) m/z 237.4 [M+H] + .
• Step-6 N-(2,5-dimethyl-4,5-dihydropyrazolo[l,5-a]pyrido[3,4-e]pyrazin-6-yl-4,4- d2)cyclopropanecarboxamide (I-19f): I-19f (1.8 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-3) using I-19e (2.0 g, 13.01 mmol) and cyclopropanecarboxamide (0.65 g, 7.6 mmol) as the starting materials. LCMS (ES) m/z 286.4 [M+H] + .
• Step-7 2, 5-dim ethyl-4, 5-dihydropyrazolo [1,5-a] pyrido [3,4-e] pyrazin-4,4-d2-6- amine (1-19): 1-19 (0.8 g) was synthesized by following procedure as described for the synthesis of 1-9 (step-4) using I-19f (1.8 g, 6.31 mmol) as the starting material. LCMS (ES) m/z; 218.4 [M+H] + .
• Step-1 ethyl l-(3-bromo-2-fluorophenyl)-lH-pyrazole-5-carboxylate (I-20b): I-
• Step-2 l-(3-bromo-2-fluorophenyl)-lH-pyrazole-5-carboxylic acid (I-20c): I-20c
• Step-3 (l-(3-bromo-2-fluorophenyl)-lH-pyrazol-5-yl)methan-d2-ol (I-20d): I-20d (4.3 g) was synthesized by following procedure as described for the synthesis of 1-19 (step-2) using I-20c (6.2 g, 21.7 mmol) as the starting material. LCMS (ES) m/z; 273.2 [M+H] + .
• Step-4 l-(3-bromo-2-fluorophenyl)-lH-pyrazole-5-carbaldehyde-d (I-20e): I-20e (2.1 g) was synthesized by following procedure as described for the synthesis of 1-5 (step-6) using I-20d (4.3 g, 15.7 mmol) as the starting material. LCMS (ES) m/z; 270.0 [M+H] + .
• Step-5 l-(l-(3-bromo-2-fluorophenyl)-lH-pyrazol-5-yl)-N-methylmethan-d2- amine (1-201): I-20f (2.0 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-5) using I-20e (2.1 g, 7.78 mmol) as the starting material. LCMS (ES) m/z; 286.1 [M+H] + .
• Step-6 6-bromo-5-methyl-4,5-dihydropyrazolo[l,5-a]quinoxaline-4,4-d2 (I-20g): I-20g (1.7 g) was synthesized by following procedure as described for the synthesis of 1-16 (step-5) using I-20f (2.0 g, 6.99 mmol) as the starting material. LCMS (ES) m/z; 266.1 [M+H] + .
• Step-7 tert-butyl (5-methyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-6-yl-4,4- d2)carbamate (I-20h): I-20h (1.3 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-20g (1.7 g, 6.39 mmol) as the starting material. LCMS (ES) m/z 303.1 [M+H] + .
• Step-8 5-methyl-4,5-dihydropyrazolo[l,5-a]quinoxalin-4,4-d2-6-amine (1-20): I-
• Step-1 l-(3-bromo-2-fluorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-lH- pyrazole (I-21b) and l-(3-bromo-2-fluorophenyl)-3-(furan-2-yl)-5-(trifluoromethyl)-lH- pyrazole (I-21c): To a stirred solution of I-21a (15.1 g, 73.2 mmol) in AcOH (150 mL) was added (3-bromo-2-fluorophenyl)hydrazine (10 g, 48.8 mmol) at room temperature and the reaction mixture was the stirred at 100 °C for 4 h.
• Step-2 l-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (I-21d) and l-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-lH-pyrazole-3-carboxylic acid (I-21e): To a stirred solution of I-41b + I-41c (17 g, 45.3 mmol) in acetone (200 mL) and water (200 mL) was added potassium permanganate (50.1 g, 317 mmol) portion wise at 0 °C. The reaction mixture was stirred at 60 °C for 3 h.
• Step-3 l-(3-bromo-2-fluorophenyl)-N-methoxy-N-methyl-3-(trifluoromethyl)-lH- pyrazole-5-carboxamide (I-21f):
• I-21f (6.0 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-3) using I-21d (6.0 g, 17 mmol) as the starting material.
• Step-4 l-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5- carbaldehyde (I-21g): I-21g (3.0 g) was synthesized by following procedure as described for the synthesis of 1-11 (step-4) using I-21f (6.0 g, 15.1 mmol) as the starting material. LCMS (ES) m/z; 337.0 [M+H] + .
• Step-5 l-(l-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-N- methylmethanamine (I-21h): I-21h (3.0 g) was synthesized by following procedure as described for the synthesis of 1-8 (step-2) using I-21g (3.0 g, 8.9 mmol) as the starting material. LCMS (ES) m/z; 352.1 [M+H] + .
• Step-6 6-bromo-5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[l,5- a]quinoxaline (I-21i): I-21i (2.0 g) was synthesized by following procedure as described for the synthesis of 1-16 (step-5) using I-21g (3.0 g, 8.52 mmol) as the starting material. LCMS (ES) m/z 332.1 [M+H] + .
• Step-7 tert-butyl (5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[l,5- a]quinoxalin-6-yl)carbamate (1-2 lj): I-21j (1.5 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-4) using I-21i (2.0 g, 6.02 mmol) as the starting material. LCMS (ES) m/z 369.2 [M+H] + .
• Step-8 5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[l,5-a]quinoxalin-6- amine (1-21): 1-21 (0.7 g) was synthesized by following procedure as described for the synthesis of 1-1 (step-5) using I-21j (1.5 g, 4.07 mmol) as the starting material.
• A-3 (2.6 g) was synthesized as described for the synthesis of A-2 using A-3a (3 g) as the starting material.
• LCMS (ES) m/z 208.0 [M+H] + .
• A-1a A-4 [00446] To a stirred solution of A-la (2.5 g, 12.6 mmol) in anhydrous DCM (50 mL) was added catalytic amount of DMF (2 to 3 drops) and oxalyl chloride (2.5 mL, 25.1 mmol) drop wise at 0 °C. The reaction mixture was then allowed to warm to room temperature over 2 h. After completion, volatiles were removed under reduced pressure and the residue was dried.
• Example 26 Preparation of 4,6-dichloro-N-methylnicotinamide (A-5): i) oxalyl chloride, DCM cat DMF rt 2 h
• A-5 (2.5 g) was synthesized as described for the synthesis of A-l using A-3a (3 g) as the starting material.
• Example 27 Preparation of 4,6-dichloronicotinamide (A-6): i) oxalyl chloride, DCM cat. DMF, rt, 2 h
• A-6 (0.14 g) was synthesized as described for the synthesis of A-4 using A-3a (0.25 g) as the starting material.
• LCMS (ES) m/z; 190.9 [M+H] + .
• Example 28 Preparation of 4-bromo-6-chloro-N-(methyl-d3)nicotinamide (A-7):
• Step-1 6-chloro-N-methyl-4-( ⁇ 2-methyl-2H,4H-chromeno[4,3-c]pyrazol-6- yl ⁇ amino)pyridazine-3-carboxamide (la): To a stirred solution of 1-1 (0.52 g, 2.58 mmol) and A-1 (0.639 g, 3.10 mmol) in propan-2-ol (3.00 mL) and water (2.00 mL) was added Zn(OAc)2 (0.759 g, 4.13 mmol) at room temperature. The reaction mixture was then stirred at 75 °C for 16 h in a sealed tube. The progress of the reaction was monitored by LCMS.
• Step-2 6-[(5-fluoropyridin-2-yl) amino]-N-methyl-4-( ⁇ 2-methyl-2H,4H- chromeno[4,3-c]pyrazol-6-yl ⁇ amino)pyridazine-3-carboxamide
• Compound 1 Argon gas was purged through a stirred suspension of la (0.4 g, 1.08 mmol), 5-fluoropyridin-2-amine (0.181 g, 1.62 mmol) and CS2CO3 (0.703 g, 2.16 mmol) in 1,4-dioxane (6.00 mL) for 15 min.
• Step-1 6-(cyclopropanecarboxamido)-N-methyl-4-((2-methyl-2,4- dihydrochromeno[4,3-c]pyrazol-6-yl)amino)pyridazine-3-carboxamide (Compound 2):
• Argon gas was purged through a stirred suspension of 6-chloro-N-methyl-4-( ⁇ 2-methyl-2H,4H- chromeno[4,3-c]pyrazol-6-yl ⁇ amino)pyridazine-3-carboxamide la (0.15 g, 0.405 mmol), cyclopropanecarboxamide (0.068 g., 0.809 mmol) and CS2CO3 (0.264 g, 0.809 mmol) in DMA (2.00 mL) for 15 min.
• Step-1 6-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)-N-(methyl-d3)nicotinamide (17a): To a stirred solution of 1-5 (4.5 g, 21.0 mmol) and A-3 (4.37 g, 21.0 mmol) in anhydrous DMA (10.0 mL) was added a 1M solution of LiHMDS (in THF) (73.5 mL, 73.5 mmol) drop wise at 0 °C. The reaction mixture was allowed to stir at the same temperature for 1 h, while monitoring reaction progress by TLC.
• LiHMDS in THF
• Step-2 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-d )nicotinamide (compound 14): Argon gas was purged through a stirred suspension of 17a (6.0 g, 15.5 mmol), cyclopropanecarboxamide (1.99 g, 23.3 mmol) and CS2CO3 (10.1 g, 31.1 mmol) in 1,4-dioxane (20 mL) for 15 min.
• Step-1 6-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (29a): To a stirred solution of 1-10 (0.5 g, 2.32 mmol) and A-2 (0.78 g, 3.72 mmol) in DMF (10.0 mL) was added NaH (60% suspension in mineral oil) (0.56 g, 13.9 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h.
• Step-2 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c][l,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
• Compound 65 Compound 65 (150 mg) was synthesized by following procedure as described for the synthesis of compound 1 (step-2) using 29a (0.34 g, 0.877 mmol) and cyclopropanecarboxamide (0.097 g, 1.14 mmol) as the starting materials.
• Step-1 6-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c][l,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide (33a): 33a (0.25 g) was synthesized by following procedure as described for the synthesis of compound 1 (step-2) using 1-12 (0.31 g, 1.43 mmol) and A-7 (0.396 g, 1.57 mmol) as the starting materials. LCMS (ES) m/z; 389.2 [M+H] + .
• Step-2 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c] [l,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide
• Compound 77 Compound 77 (27 mg) was synthesized by following procedure as described for the synthesis of compound 1 (step-2) using 33a (0.25 g, 0.643 mmol) and cyclopropanecarboxamide (0.066 g, 0.771 mmol) as the starting materials.
• LCMS (ES) m/z 438.3 [M+H] + .
• Example 34 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-(l- hydroxycyclopropane-l-carboxamido)-N-(methyl-d3)nicotinamide (Compound 21):
• Step-1 methyl l-(benzyloxy)cyclopropane-l-carboxylate (50b): To a stirred solution of 50a (1.54 mL, 17.2 mmol) in anhydrous DMF (15 mL) was added sodium hydride (60% suspension) (1.32 g, 34.4 mmol) at 0 °C and stirred for 30 min. To this was then added benzyl bromide (2.60 mL, 20.7 mmol 1) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 h. It was then quenched with addition of saturated NaHCCb solution (30 mL) and extraction was carried out using (50 mL x 3).
• Step-2 l-(benzyloxy)cyclopropane-l-carboxylic acid (50c): To a stirred solution of 50b (1.20 g, 5.82 mmol) in MeOH (10.0 mL) and THF (10 mL) was added 8.0 mL of aqueous solution of sodium hydroxide (0.7 g, 17.46 mmol) and the reaction mixture was stirred at room temperature for 2 h. After completion (as indicated by TLC), volatiles were removed under reduced pressure and diluted with water (15 mL). It was then acidified by slow addition of 2N aqueous HC1 solution.
• Step-3 l-(benzyloxy)cyclopropane-l-carboxamide (50d): To a stirred solution of
• Step-4 6-(l-(benzyloxy)cyclopropane-l-carboxamido)-4-((2,5-dimethyl-4,5- dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide (50e): 50e (0.2 g) was synthesized by following procedure as described for the synthesis of compound 1 (step- 2) using 33a (0.3 g, 0.78 mmol) and 50d (0.18 g, 0.933 mmol) as the starting materials. LCMS (ES) m/z 541.2 [M+H] + .
• Step-5 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-(l- hydroxycyclopropane-l-carboxamido)-N-(methyl-d3)nicotinamide (compound-21): To a stirred solution of 50e (0.27 g, 0.499 mmol) in MeOH (10.0 mL) and THF (10.0 mL) was added 10% Pd/C (100 mg) at room temperature. The reaction mixture was then stirred under hydrogen atmosphere (balloon) for 16 h. After completion, the catalyst was filtered off through celite bed and washed with MeOH (20 mL x 3).
• Step-1 ethyl 2-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)pyrimidine-5-carboxylate (51b): To a solution of 1-11 (0.5 g, 2.33 mmol) and 51a (0.67 g, 3.03 mmol) in ACN (15 mL) was added DIPEA (0.62 mL, 3.50 mmol); and the reaction mixture was stirred for 3 h (reaction progress was monitored by TLC) at room temperature.
• Step-2 ethyl 2-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)amino)pyrimidine-5-carboxylate (51c): Argon gas was purged through a stirred suspension of 51b (0.5 g, 1.25 mmol), cyclopropanecarboxamide (0.22 g, 2.51 mmol) and CS2CO3 (1.23 g, 3.76 mmol) in 1,4-dioxane (8.00 mL) for 15 min.
• Step-3 2-amino-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)pyrimidine-5-carboxylic acid (51d): To a stirred solution of 51c (0.38 g, 0.85 mmol) in THF:EtOH (5:5 mL) was added an aqueous solution of LiOHEhO (0.11 g, 2.55 mmol, in 2 mL water) at room temperature. It was then stirred at 80 °C for 6 h, while monitoring reaction progress by LCMS.
• Step-4 2-amino-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (51e): To a stirred solution of 51d (0.2 g, 0.57 mmol) and methan-d3-amine hydrochloride (0.08 g, 1.14 mmol) in DMF (3 mL) was added DIPEA (0.5 mL, 2.85 mmol) and HATU (0.43 g, 1.14 mmol). The reaction mixture was stirred at room temperature for 2 h.
• Step-5 2-(N-(cyclopropanecarbonyl)cyclopropanecarboxamido)-4-((2,5-dimethyl- 4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-d3)pyrimidine-5- carboxamide (51f): To a stirred solution of 51e (0.13 g, 0.35 mmol) in anhydrous DCM (10 mL) was added DIPEA (0.13 mL, 0.70 mmol), DMAP (5 mg, 0.03 mmol) and cyclopropanecarbonyl chloride (0.04 g, 0.39 mmol) sequentially.
• reaction mixture was stirred at room temperature for 2 h, while monitoring reaction progress by LCMS. After completion, water (10 mL) was added to it and extraction was carried out using DCM (3 x 15 mL). The combined organic extracts were washed with water (10 mL), brine (15 mL), dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure.
• Step-6 2-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo [4,3-c] quinolin-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide
• Compound 22 To a stirred solution of 51f (0.15 g, 0.29 mmol) in MeOH (10 mL) was added K2CO3 (50 mg, 0.33 mmol) and the reaction mixture was stirred at room temperature for 2 h. After complete consumption of starting material, K2CO3 was filtered off through celite and washed with MeOH.
• Step-2 tert-butyl (5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)carbamate (52c) & tert-butyl (5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinolin-6-yl)carbamate (52d): 1.05 g of mixture of 52c and 52d was synthesized by following procedure as described for the synthesis of 1-11 (step-9) using mixture of 52a and 52b (1.05 g, 2.33 mmol) as the starting material. LCMS (ES) m/z 431.0 [M+H] + .
• Step-3 5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-amine (52e) & 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-4,5- dihydro-lH-pyrazolo[4,3-c]quinolin-6-amine (521): To a stirred solution (52c + 52d) (0.65 g, 1.51 mmol) in n-BuOH (2.0 mL) were added water (1.0 mL) and sodium hydroxide (1.21 g,
• Step-4 6-chloro-N-(methyl-d3)-4-((5-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-
• Step-5 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)nicotinamide (52i) & 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl- l-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-lH-pyrazolo[4,3-c]quinolin-6- yl)amino)nicotinamide (52j): 0.3 g of mixture of 52i and 52j was synthesized by following procedure as described for the synthesis of compound 17 (step-2) using mixture of 52g and 52h (0.25 g, 0.498 mmol) as the starting material.
• LCMS (ES) LCMS (
• Step-6 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro- 2H-pyrazolo[4,3-c]quinolin-6-yl)amino)nicotinamide
• Compound 23 To a stirred solution of (52i + 52j) (250 mg, 0.454 mmol) in DCM (10.0 mL) was added trifluoroacetic acid (2.50 mL) at 0 °C under N2 atmosphere. It was then stirred at room temperature for 2 h. After completion, volatiles were removed under reduced pressure and saturated sodium bicarbonate solution (10 mL) was added to the residue.
• Example 37 Preparation of methyl 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5- dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)nicotinate (Compound 60): cyclopropanecarboxamide Cs 2 C0 3 , Xantphos Pd 2 (dba) 3 , 1 ,4-dioxane 130 °C, 3 h
• Step-1 6-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6- yl)amino)nicotinic acid (53a): To a stirred solution of 1-11 (0.3 g, 1.4 mmol) and A-3a (0.4 g,
• Step-2 methyl 6-chloro-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin- 6-yl)amino)nicotinate (53b): To the solution of 53a (0.125 g, 0.338 mmol) in DCM (10.0 mL) was added N,N'-dicyclohexylmethanediimine (0.209 g, 1.01 mmol), DMAP (4.13 mg, 0.033 mmol) and MeOH (0.14 mL, 3.38 mmol). It was then stirred at room temperature for 16 h.
• Step-3 methyl 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)amino)nicotinate (Compound 60): Compound 60 (15 mg) was synthesized by following procedure as described for the synthesis of compound 1 (step-2) using 53b (90 mg, 0.234 mmol) as the starting material. LCMS (ES) m/z 433.2 [M+H] + .
• Example 38 6-chloro-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)nicotinamide (34a):
• Step-1 6-chloro-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)nicotinamide (34a): 34a (1.3 g) was synthesized by following procedure as described for the synthesis of compound 14 (step-1) using 1-14 (1.0 g, 4.38 mmol) and A-3 (1.37 g , 6.57 mmol) as the starting material. LCMS (ES) m z; 400.2 [M+H] + .
• Racemate 34a (1.3 g) was resolved by chiral HPLC [(Column: CHIRALPAK IC (250 mm x 30 mm x 5 pm); Mobile phase: n-Hexane:IPA with 0.1% DEA (50:50); Flow rate: 40 mL/min)] to afford two enantiomers (34B (0.49 g): peak-1; R t : 6.96 min and 34C (0.5 g): peak- 2; R t : 8.54 min ⁇ , which were carried forward without their absolute configuration determination.

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